The long-term objective of the study team is to deliver, with maximal treatment response and minimal treatment exposure, a branched chain amino acid (BCAA) dietary supplement that we have developed as a treatment for tardive dyskinesia (TD) to patients with the disorder. We hope to develop from the proposed study a rational dose strategy for future large-scale efficacy trials of this treatment. The Specific Aims for the proposed study are (l) to obtain efficacy data, (2) to estimate a dose response curve, and (3) obtain control data for the use of this supplement as a treatment for TD. These aims will be accomplished by (a) conducting a three week double-blind, placebo-controlled trial in which 48 male psychotic patients with TD will be randomized to one of four groups: low (BCAA 50 mg/kg t.i.d.), middle (BCAA 150 mg/kg t.i.d), high (BCAA 209 mg/kg t.i.d), or placebo; (b)testing the hypothesis that the proportion of responders to the treatment (patients who experience a 50% or more decrease in TD movement counts) in the high dose group will be significantly higher than the proportion of responders in the placebo group; (c) estimating the dose response curve from the treatment response in each of the four study groups, (d) collecting control information throughout the trial on gastrointestinal complaints, plasma large neutral amino acid levels, plasma glucose levels, plasma neuroleptic levels as well as information on psychiatric and cognitive status, and (e) addressing the issues of adaptive changes in treatment response and duration of treatment effect for the three-week trial period by evaluating the treatment responses data at the first day of treatment and after one, two and three weeks of treatment. The parent application of the present proposal robustly demonstrated that, following a dietary challenge of phenylalanine (Phe), psychotic males with TD had significantly higher plasma Phe levels and Phe/large neutral amino acid (LNAA) ratios than patients without TD. This suggested that LNAA metabolism and TD were related, and beyond that, that TD might be responsive to dietary manipulation. Furthermore, earlier we had found unexpectedly a complete remission of symptoms in 50% of TD patients after a meal enriched with BCAA (isoleucine, leucine, and valine). A plasma marker of that behavioral response was a significant increase in valine)LNAA ratio. As LNAA ratios are an index of the availability of an amino acid to the brain, this finding suggested a central effect of BCAA on TD symptoms. Further support was provided by the finding that in 209 psychotic men a Phe challenge produced significantly higher plasma BCAA indices in TD-No subjects than in TD-Yes subjects. Thus, greater Phe indices are associated with TD-Yes, and greater BCAA indices with TD-No. Most importantly, we have completed a two-week trial of the 209 mg/kg dose of the BCAA treatment and found that 100% of the patients (4 of 4) responded in terms of the above criterion. TD movement counts, in fact, decreased by 99%, 71%, 73%, and 69%, respectively. This work has important public health implications since TD, which is often a source of social stigmatization, afflicts large numbers of psychiatric patients. For example, a public sector cohort (n=223) that we have followed longitudinally has a most recent TD point prevalence of 58%, and 40% of these have persistent TD. Although the newer, less dyskinetogenic atypical neuroleptics hold promise of diminishing incidence of TD, they come too late for some, are ineffective or impractical for some others, and are not available to all.